Cancer is a leading cause of death in in the United States (˜25% of the population), and the vast majority of these cancers are of epithelial cell origin (Jemal, A., et al. (2007) CA: A Cancer Journal for Clinicians 57, 43-66). Over 90% of cancer deaths related to solid malignancies are due to metastatic dissemination of cancer to secondary organs (Gupta, G. P. and Massague, J. (2006) Cell 127, 679-695; Valastyan, S., et al. (2011) Genes Dev. 25, 646-659). A hallmark of tumor malignancy, and a requirement for metastasis, is the acquired ability of cells to detach from the primary tumor mass and invade into surrounding stromal tissues. This capacity is highly associated with the loss of expression of epithelial cadherin (E-cadherin), since most solid tumors are carcinomas that are derived from epithelial cells/tissues. E-cadherin is a key adhesion molecule that plays a pivotal role in maintaining cell polarity, epithelial architecture, and cell differentiation. The epithelial-mesenchymal transition (EMT) is a reversible process whereby epithelial cells undergo coordinated reprogramming of their gene expression and lose the epithelial characteristics of tight cell-cell adhesiveness and apical-basal polarity, while gaining mesenchymal properties, including increased motility and capacity for invasion through the basement membrane (Valastyan, S., et al. (2011) Genes Dev. 25, 646-659; Katsuno, Y., et al. (2013) Current Opinion in Oncology 25, 76-84; Lim, J., et a. (2012) Development 139, 3471-3486). Gene expression profiling has indicated that de-differentiated cancer cells combine the EMT properties with a stem-cell like phenotype.
As a feature of the reprogramming of gene expression during EMT, an invariable hallmark of EMT is the marked decrease of E-cadherin expression and function. Alterations in E-cadherin expression have a major impact on cell-cell interactions, resulting in disturbed epithelial tissue homeostasis. Indeed, upon loss of functional E-cadherin, cells become more prone to acquire a motile and invasive phenotype, accounting for the metastatic potential of many epithelial cancer cells. The expression of E-cadherin is frequently lost in human cancers, and while this can be due to mutational inactivation (as in familial gastric cancer syndrome), more frequently the loss of expression is due to transcriptional inhibition or silencing (as occurs in EMT). Several developmentally important transcriptional regulatory proteins, such as ZEB1, ZEB2, Snai1, Snai2/SLUG, TWIST 1, and E47/TCF3, induce EMT and are directly involved in repression of E-cadherin expression (Wang, Y. and Shang, Y. (2013) Experimental Cell Research 319, 160-169).
Despite knowledge that the acquisition of EMT features is associated with chemoresistance, often leading to recurrence and metastasis after standard chemotherapeutic treatment (Iwatsuki, M., et al. (2010) Cancer Sci. 101, 293-299), very few experimental therapeutic agents are known to inhibit the EMT phenotype. These needs and other needs are addressed by the present invention.